The role of neurotransmitters in the development of Parkinson's disease-related psychosis.

Psychotic symptoms are common, disabling non-motor features of Parkinson's disease (PD). Despite noted heterogeneity in clinical features, natural history and therapy response, current dogma posits that psychosis generally progresses in a stereotypic manner through a cascade of events that begins with minor hallucinations and evolves to severe hallucinations and delusions. Further, the occurrence of psychotic symptoms is believed to indicate a poor prognosis. Here we propose a classification scheme that outlines the pathogenesis of psychosis as it relates to dysfunction of several neurotransmitter systems. We hypothesize that several subtypes exist, and that PD psychosis is not consistently indicative of a progressive cascade and poor prognosis. The literature was reviewed from 1990 to 2017. An overview of the features of PD psychosis is followed by a review of data indicating the existence of neurotransmitter-related subtypes of psychosis. We found that ample evidence exists to demonstrate the presence of multiple subtypes of PD psychosis, which are traced to dysfunction of the following neurotransmitter systems: dopamine, serotonin and acetylcholine. Dysfunction of each of these systems is recognizable through their clinical features and correlates, and the varied long-term prognoses. Identifying which neurotransmitter system is dysfunctional may help to develop targeted therapies. PD psychosis has various subtypes that differ in clinical features, underlying pathology and pathophysiology, treatment response and prognosis. A novel classification scheme is presented that describes the clinical subtypes with different outcomes, which could lead to the development of targeted therapies. Future research should focus on testing the viability of this classification.

Trajectories of recovery in depressed Parkinson's disease patients treated with paroxetine or venlafaxine.

INTRODUCTION: Depression is considered a syndrome with a constellation of symptoms that are frequently categorized into 3 domains including affective, somatic and cognitive. There has been limited research into the domain specific magnitude or relative timing of treatment response in patients with Parkinson's disease (PD). In addition, antidepressant trials involving patients with PD have demonstrated a similar robust placebo response to that seen in other populations. However, the timing of the placebo response has not been carefully studied. METHODS: We studied differential responses to antidepressant treatment in affective, somatic and cognitive domains of depression. Patients were treated for twelve weeks with placebo, venlafaxine or paroxetine as part of the Study of Antidepressants in Parkinson's Disease (SAD-PD) randomized controlled trial. Depressive symptoms were evaluated with three commonly used rating scales. RESULTS: All symptom domains improved during the study period, There was a significant placebo effect, especially in the first two weeks that had diminished by week 12. Compared to placebo, the affective symptoms significantly improved during treatment as early as week 4, followed by the somatic symptoms of depression in week 6 and cognitive symptoms in week 8. The largest response was seen in the affective domain. CONCLUSION: In depressed PD patients treated with venlafaxine or paroxetine, affective symptoms improved first, followed by somatic symptoms and cognitive symptoms. These findings could guide patient counselling and increase patient compliance by informing about the expected treatment responses. The substantial placebo effect underlines the importance of a sufficiently long study period in future studies.

Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations.

A role of the caudate nucleus in depression has been suggested from relevant clinical conditions, such as patients with Huntington's disease or caudate infarcts, as well as animal studies. Correlations of caudate nucleus disease with depressive symptoms have been limited to autopsy studies and cases of gross pathological disorder, such as large infarcts. We used serial axial high-field magnetic resonance images and an unbiased stereological technique to estimate the volumes of the caudate nuclei in 50 patients who met DSM-III criteria for major depression (23 men, 48.3 +/- 17 years old) in comparison with 50 age- and gender-matched normal controls free of major neurological and psychiatric disorders. Depressed patients had smaller caudate nucleus volumes (5.2 +/- 1.6 cm3) compared with controls (6.2 +/- 1.7 cm3). Right and left caudate nucleus volumes were smaller in depressed patients compared with controls. Age was negatively correlated with caudate nucleus volumes in depressed patients as well as in controls. Caudate nucleus volumes in depressed patients were inversely correlated with the bicaudate and bifrontal indices. These results may be the first demonstration of diminished caudate nucleus volumes in depression and suggest a role for the caudate nucleus in the pathogenesis of major depression.

Platelet [3H]-imipramine binding and leukoencephalopathy in geriatric depression.

We examined the relationship between platelet [3H]-imipramine binding and leukoencephalopathy as assessed by 1.5 Tesla Magnetic Resonance Imaging (MRI) in 21 elderly depressed patients who satisfied DSM-III criteria for major depression. Both drug-free platelet [3H]-imipramine binding and brain MRI studies were obtained during the same episode of depression. Our findings show a significant inverse relationship between frequency of subcortical hyperintensity (SCH) and the number (Bmax) of platelet [3H]-imipramine binding sites. Patients with Bmax less than 850 fmol/mg protein had significantly larger SCH compared with patients with a higher Bmax. These data provide further support to the potential use of platelet [3H]-imipramine binding studies and brain MR imaging as diagnostic adjuncts in geriatric depression and suggest, moreover, that these two biological markers may be linked in geriatric patients with depression.

Magnetic resonance findings in patients with early-onset Alzheimer's disease.

The magnetic resonance scans of 22 patients with early-onset Alzheimer's disease (AD) were compared to 16 age-matched neurologically normal controls for the presence of white matter subcortical hyperintensities (SCH) and periventricular hyperintensities (PVH). Patients with AD were significantly more likely to have evidence of PVH (p less than 0.01) than age-matched controls. There was no significant difference between the two groups in either the frequency of SCH or the size of the largest lesion. Within the AD group, there was no difference demonstrated in the location of the SCH, either in the anterior-posterior plane or between the two hemispheres. Patients with AD more frequently demonstrated ventriculomegaly (p less than 0.001) and sulcal widening (p less than 0.05) compared with controls. This study suggests that the SCH seen in early-onset AD patients on MRI are related more to the aging process than to the AD process and that the increased frequency of PVH may have a relationship to the disease process.

Magnetic resonance imaging correlates of depression in early- and late-onset Alzheimer's disease.

BACKGROUND: Depressive symptoms are frequent complications of Alzheimer's disease (AD). We hypothesized that AD patients with depression would be more likely than nondepressed AD patients to show deep white-matter, subcortical gray-matter, and periventricular hyperintensities on magnetic resonance imaging (MRI). METHODS: In a retrospective study of 31 AD patients, depression was characterized by clinical diagnosis (DSM-III-R major depression, depressive symptoms, or no depression), a clinician-rated depression scale, and informant ratings of premorbid (before memory disorder) as well as current depression using the NEO Personality Inventory (NEO-PI), and related to qualitative and quantitative ratings of MRI hyperintensities. RESULTS: In contrast to reports in nondemented elderly patients, there was no relationship between clinical diagnosis of major depressive episode and hyperintensities; however, clinician-rated depressive symptoms were higher in subjects with large anterior hyperintensities. In the early-onset AD group only, MRI abnormalities were related to greater premorbid depression, and less increase in depression after the onset of dementia, as rated by informants on the NEO-PI. CONCLUSIONS: Results highlight the need to consider early- and late-onset AD separately when assessing relationships between personality and MRI abnormalities, and to consider premorbid personality style when drawing conclusions about the etiology of depressive features seen in AD.

Hyperintense lesions on magnetic resonance images in bipolar disorder.

BACKGROUND: To examine the magnetic resonance (MR) images of bipolar patients across a wide age range for the presence of hyperintense lesions compared to age- and gender-matched control subjects. METHODS: Consecutive admissions to a mood disorders unit over a 2-year period were evaluated retrospectively for the presence of bipolar disorder by DSM-III-R criteria and whether they received an MR scan. Bipolar patients (n = 70, mean age = 49.9 +/- 19.7 years) were age- and gender-matched to control subjects (n = 70, mean age = 53.2 +/- 18.1 years) and the MR scans were rated to assess for the presence of hyperintensites. RESULTS: Compared to control subjects, the bipolar patients demonstrated hyperintense lesions in the subependymal region, subcortical gray nuclei, and the deep white matter. CONCLUSIONS: Hyperintense lesions in bipolar patients are found in both the subcortical white matter and gray nuclei and may play an important role in the etiology of bipolar illness.

Assessment of posterior fossa structures with midsagittal MRI: the effects of age.

Midsagittal magnetic resonance (MR) images of 36 normal volunteers, ranging in age from 26 to 79 years, were used to evaluate the effects of age on the size of posterior fossa structures (cerebellar vermis, midbrain, pons, medulla and fourth ventricle). Our results demonstrate a highly statistically significant age-related decline in the cross-sectional area of the midbrain (r = -.44, p less than 0.007), a less prominent decline in the area of the anterior cerebellar vermis (r = -.33, p less than 0.05) and striking intercorrelations between the dimensions of the pons, medulla and cerebellar vermis. To the best of our knowledge, this is the first MRI demonstration of midbrain atrophy during aging in normal adults.

Controlled investigation of the amobarbital interview for catatonic mutism.

OBJECTIVE: Clinical reports over the last 60 years suggest that the amobarbital interview is effective in relieving catatonic symptoms. This has never been substantiated with methodologically sound trials. The authors postulated that a randomized blind comparison of intravenous amobarbital and saline would demonstrate the superiority of amobarbital in relieving catatonic mutism. METHOD: The subjects were 20 inpatients with catatonic mutism. They were randomly assigned to either saline (N = 10) or a 5% amobarbital solution (N = 10), and the infusions were administered intravenously at a rate of 1 cc/min or less over 10 minutes by a blinded physician. A second blinded physician administered a semistructured interview during the infusion to control for the effect of suggestion. A third blinded physician rated patient responsiveness, reactivity, and arousal. Any patient who was unresponsive to the initial infusion was crossed over to the other infusion. Interviews were videotaped for determination of interrater reliability. RESULTS: In the initial infusions, six of 10 patients responded to amobarbital and zero of 10 responded to saline. Four of the saline nonresponders responded when given amobarbital. Response was evident by the 4th minute of the amobarbital infusion. Interrater reliability was high. The responders and nonresponders differed significantly in the variance of the weight-adjusted amobarbital dose, and the responders tended to be older and female. CONCLUSIONS: Intravenous amobarbital is superior to saline in relieving catatonic mutism, although only 50% of these patients responded. The nonresponders were distinguished from the responders by a greater variance in the weight-adjusted dose of amobarbital.

Alzheimer's disease in the National Academy of Sciences-National Research Council Registry of Aging Twin Veterans. III. Detection of cases, longitudinal results, and observations on twin concordance.

OBJECTIVES: To detect cases of Alzheimer's disease (AD) in a large population of twins living throughout the United States and to examine concordance for AD in twins as a function of age and genotype for apolipoprotein E (APOE). SETTING: Nationwide survey. DESIGN: Multistage screening and field evaluation beginning with two telephone interviews and culminating with laboratory tests, longitudinal neuropsychological measures, physician examination, and diagnostic consensus among experts. PARTICIPANTS: Membership in 1990-1991 of intact pairs in the National Academy of Sciences--National Research Council Registry of veteran twins, then aged 62 to 73 years. MAIN OUTCOME MEASURES: Completeness of case detection was examined in collateral studies. Zygosity and APOE genotypes were determined by restriction mapping. Concordance was calculated by the proband method. RESULTS: Ninety subjects who screened positively for AD were studied in person, and 60 whose differential diagnoses included AD were followed up, as were their co-twins. Sensitivity of screening was estimated at greater than 99%, but 24% of subjects refused participation after initial screening. Seven of 38 diagnoses of AD have been confirmed at autopsy, and 31 other subjects eventually met criteria for probable or possible AD (prevalence estimate, 0.42%, 95% confidence interval, 0.29% to 0.56%), with good interrater reliability (intraclass r = .86). Excluding one discordant pair with unknown zygosity, concordance rates were 21.1% (4/19) for monozygotic and 11.1% (2/18) for dizygotic probands. Concordance was 50% for twins sharing the epsilon 4/epsilon 4 genotype at APOE, but there were no affected co-twins of 15 probands with onset before age 70 years, no epsilon 4 allele, and no family history of AD. The mean (SD) period of discordance in the latter pairs was 11.3 (3.3) years. CONCLUSIONS: The multistage case-detection approach achieved reliable and valid diagnoses of AD with high apparent sensitivity but substantial attrition after initial screening. Genetic influences in AD at this age are limited, except among homozygotes for allele epsilon 4 at APOE. Subjects with early-onset AD who lack the epsilon 4 allele are not rare, and their condition appears to have little genetic influence. They should be ideal for studies on environmental cause of AD.

Cognitive impairments in advanced PD without dementia.

OBJECTIVE: To determine the nature and frequency of cognitive impairments in nondemented patients with advanced PD and their relationship to other variables potentially predictive of neuropsychological performance. METHODS: The neuropsychological performance of nondemented, nondepressed patients with idiopathic PD (n = 61) was quantified with respect to clinically available normative data. The relationship of neuropsychological measures to motor symptoms, age, years of education, disease duration, age at disease onset, disease deterioration rate, and dopaminergic therapy was assessed. RESULTS: Impairment was most frequent on measures sensitive to frontal lobe function (67% on Wisconsin Card Sorting Test number of categories, 30% on letter fluency, 30% on verbal learning). Poorer performance on multiple neuropsychological measures was related to greater overall motor abnormality (total Unified Parkinson's Disease Rating Scale score), increased bradykinesia on medication, older age, longer disease duration, and reduced education. CONCLUSIONS: Even in the absence of dementia or depression, patients with advanced PD are likely to show clinically significant impairments on neuropsychological measures sensitive to changes in dorsolateral prefrontal regions participating in cognitive basal ganglia-thalamocortical circuits.

Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin control study.

We conducted a co-twin control study among 50 elderly twin pairs with onsets of Alzheimer's disease (AD) separated by 3 or more years. Twenty-three male pairs (46%) were screened from the (U.S.) National Academy of Sciences-National Research Council Registry (NAS-NRC Registry) of World War II veteran twins; others (mostly women) had responded to advertisements or were referred from AD clinics. Twenty-six pairs (52%) were monozygous. The onset of AD was inversely associated with prior use of corticosteroids or ACTH (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.06 to 0.95; p = 0.04). Similar but weaker trends were present among pairs discordant for history of arthritis or for prior daily use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. The association was strongest when we combined use of steroids/ACTH or NSAIDs post hoc into a single variable of anti-inflammatory drugs (AIs) (OR, 0.24; CI, 0.07 to 0.74; p = 0.01). The inverse relation was strong in female (volunteer) twin pairs but was not present in the younger men from the NAS-NRC Registry. AIs had typically been taken for arthritis or related conditions, but a similar result was apparent after controlling statistically for the arthritis variable (OR, 0.08; CI, 0.01 to 0.69; p = 0.02). AIs have been proposed as a means of retarding the progression of AD symptoms, and these data suggest that AIs may also prevent or delay the initial onset of AD symptoms. Because of limitations in the case-control method, our results require corroboration with hypothesis-driven research designed to control bias and confounding.

Neuropsychological and psychiatric sequelae of pallidotomy for PD: clinical trial findings.

OBJECTIVE: To evaluate the neuropsychological and psychiatric sequelae of unilateral posterior pallidotomy for treatment of PD. METHODS: Patients with idiopathic PD completed baseline and 3- and 6-month assessments after random assignment to an immediate surgery (n = 17) or medical management (n = 16) group. RESULTS: Compared with the medical management group, the immediate surgery group with single lesions centered on the posterior internal pallidum showed superior naming and response inhibition, better verbal recall at 6 months, but greater distractibility, a tendency toward lower phonemic fluency, and a transient (3 months' only) semantic fluency deficit. The group with left lesions had more neuropsychological deficits than the group with right lesions or the medical management group, although these occurred mainly at 3 (but not 6) months. At 6 months, the patients with left lesions showed better verbal memory retention than the patients with right lesions. On most measures, the pattern of individual clinical change did not differ as a function of surgery or lesion laterality, with the exception of a higher frequency of decline in phonemic fluency in the patients with left lesions at 6 months. Although psychiatric status did not change overall, a history of depression tended to increase the risk of a depressive episode following surgery. CONCLUSIONS: Well-targeted, uncomplicated, unilateral pallidotomy does not produce overall neuropsychological or psychiatric change, although there are subtle changes on specific measures sensitive to frontal lobe function.

Dopaminergic inhibition of adenylate cyclase correlates with high affinity agonist binding to anterior pituitary D2 dopamine receptors.

Dopamine (DA) and the dopaminergic agonists n-propylnorapomorphine (NPA), 2-amino-6,7-dihydroxytetrahydronaphthalene (ADTN) and apomorphine (APO) inhibit forskolin-stimulated adenylate cyclase activity in a dose-dependent fashion by more than 40% in membrane preparations of the porcine anterior pituitary gland. These agonists exhibit apparent dissociation constants that follow an expected dopaminergic order of potency (NPA greater than ADTN greater than or equal to APO greater than DA). The inhibition is dependent on guanine nucleotides and is reversible by dopaminergic antagonists (spiroperidol greater than (+)-butaclamol much greater than (-)-butaclamol). The potencies of these agonists in inhibiting forskolin-stimulated adenylate cyclase activity correlate with the agonist dissociation constants (KH) for binding to the high affinity receptor state (RH) in porcine anterior pituitary membranes (De Lean et al., Mol. Pharmacol. 1982, 22, 290-297) and the EC50 for inhibition of prolactin release from rat anterior pituitary cells in culture (Caron et al., J. Biol. Chem. 1978, 253, 2244-2253). Furthermore, the intrinsic activities of dopamine and the other agonists for inhibition of forskolin-stimulated adenylate cyclase are similar and correlate well with the ability of these agents to induce a comparable proportion (50%) of the receptor in a high affinity state. Together these data provide additional support for the physiological relevance of the high affinity agonist binding state of the D2 receptor in mediating the decrease in prolactin secretion via attenuation of adenylate cyclase.

Epidemiology, etiology, and treatment of geriatric mania.

Few prospective studies have focused on elderly patients with mania, despite the rapidly aging population and the difficulties encountered in treating older patients with manic symptoms. Retrospective studies generally have found that the number of new cases of mania and the prevalence of mania in the population decrease with age, although there is evidence to contradict this widely held belief. The diagnosis of mania in the elderly is confounded by the overlap of manic symptoms with other syndromes that occur with aging, including dementia, delirium, and medical illnesses. The treatment of mania is more difficult in the elderly, and new treatments such as the atypical antipsychotics and the anticonvulsants take on a more important role in treatment regimens for older patients.

A magnetic resonance image study of age-related changes in human putamen nuclei.

Putamen nuclei were assessed in 36 normal volunteers using magnetic resonance imaging and a systematic sampling method. There was a significant decrease in the volume of the putamen nuclei with advancing age (r = -0.74, p less than 0.0001), and an associated decline in the volume of the caudate nuclei (r = 0.60, p less than 0.0001). The implications of these findings in age-associated motor abnormalities are discussed.

Proton spectroscopy of human brain: effects of age and sex.

1. The present study was done to assess the brain metabolites measured by proton magnetic resonance spectroscopy (MRS) in normal individuals. 2. Proton spectroscopy STEAM voxel technique with chemical shift imaging was used to provide localized metabolic information from the brains of 34 normal volunteers (15 males) between the ages of 21 and 75 years. 3. Choline, Creatine and N-acetyl aspartate (NAA) was lower in white matter than gray matter. Choline/NAA and choline/creatine ratios were also lower in white matter. The choline, creatine and NAA were lower in older subjects in the voxel representing cortical and subcortical gray matter. There were no differences between males and females. 4. This preliminary study suggests that age matching is essential for comparative studies of disease states using proton MRS.

Pituitary abnormalities in eating disorders: further evidence from MRI studies.

1. The frequent occurrence of hypothalamo-pituitary dysfunction in patients with eating disorders as well as prior reports that nutritional and endocrine status influence pituitary morphology, led us to hypothesize that pituitary size and shape may be altered in patients with eating disorders. 2. Magnetic resonance imaging (MRI) does not use ionizing radiation and is currently one of the most feasible modalities available to study the pituitary gland in vivo. Using MRI, we have previously reported in a preliminary study that female patients with eating disorders had significantly smaller pituitary glands than controls. In addition MRI excluded any pituitary mass lesions. 3. In this report, we confirm our previous MRI findings and provide further evidence of pituitary abnormalities in an expanded sample of eating disorder patients. Preliminary data on pituitary volume estimates from MRI scans are provided for a subset of patients and controls.

Morphometric changes of the human midbrain with normal aging: MR and stereologic findings.

PURPOSE: To determine the effects of age on estimated midbrain volume. PATIENTS AND METHODS: T2-weighted MR imaging and an unbiased stereologic method were used in 75 volunteers; the subjects ranged in age from 21 to 82 years and were without any significant neurologic or psychiatric disorders. RESULTS: Age was negatively correlated with estimated midbrain volume (R = -.39, P less than .0005), with the anteroposterior diameter through the substantia nigra (R = -.33, P less than .004) and with the interpeduncular distance (R = -.24, P less than .04). The linear measurements for the right and left side were almost identical. These findings are consistent with prior reports of nigrostriatal degeneration with increasing age. Furthermore, they suggest a close symmetry of age-related changes between the right and left side in normal subjects. CONCLUSIONS: Volumetric and linear measurements of midbrain morphology with MR may prove useful in the investigation of neurologic disorders such as Parkinson disease.

Interuncal distance measurements in healthy volunteers and in patients with Alzheimer disease.

PURPOSE: To evaluate further the clinical utility of the interuncal distance (IUD) measured from axial MR scans as a reflection of hippocampal atrophy. METHODS: The IUD measured from the axial MR scans of 17 healthy control subjects was correlated with the volume of the amygdala hippocampal complex obtained from coronal MR images. The IUD was also measured on axial MR scans in 12 patients with possible or probable Alzheimer disease. RESULTS: The correlation between the total amygdala hippocampal volume and the IUD was insignificant for control subjects (r = -0.38, P = .13). When analysis of covariance was performed with the IUD as the dependent variable and age and diagnosis as the independent variables, overall R2 was 0.25. Age (F = 5.02, df = 1, P = .034), but not diagnosis (F = 0.02, df = 2, P = .88), had a significant effect. CONCLUSIONS: The IUD has no significant correlation with the amygdala hippocampal volume. The IUD appears to be a better measure of overall brain volume, which changes with age. In our patient population diagnosed with mild to moderate Alzheimer disease, the IUD measurement was not found to be useful in distinguishing their scans from those of the volunteers.